Effectiveness of Lithium Plus Optimized Medication in Treating People With Bipolar Disorder (LiTMUS)

• Overall Change in Bipolar Illness Severity as Measured by Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Score [ Time Frame: Relevant time points: baseline and week 24 ] [ Designated as safety issue: No ]

  Scale: Clinical Global Impression for Bipolar Disorder Severity (CGI-BP-S) Construct: This scale holistically measures severity of a participant's depression, mania, and overall illness.

  Range: 0- not assessed, 1-normal (not at all ill), 2- borderline mentally ill, 3- mildly ill, 4- moderately ill, 5- markedly ill, 6- severely ill, 7- among the most extremely ill patients.

• Number of Necessary Medication Adjustments [ Time Frame: Measured over 6 months ] [ Designated as safety issue: No ]

  Metric Definition (Necessary Clinical Adjustments (NCA)): Medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. This was determined with the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making.

  Range: whole numbers

  Relevant time points: Weeks 2, 4, 6, 8, 12, 16, 20, and 24.

• Overall improvement in bipolar illness severity as measured by the CGI-BP-S [ Time Frame: Measured over 6 months ] [ Designated as safety issue: No ]
• Number of Necessary Medication Adjustments [ Time Frame: Measured over 6 months ] [ Designated as safety issue: No ]

• Symptoms as Measured by the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) and the Young Mania Rating Scale (YMRS) [ Time Frame: Measured over 6 months ] [ Designated as safety issue: No ]
• Quality of Life as Measured by Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) [ Time Frame: Measured over 6 months ] [ Designated as safety issue: No ]
• Suicidality [ Time Frame: Measured over 6 months ] [ Designated as safety issue: Yes ]

• Symptoms as measured by QIDS-SR and YMRS. [ Time Frame: Measured over 6 months ] [ Designated as safety issue: No ]
• Quality of life as measured by Q-LES-Q [ Time Frame: Measured over 6 months ] [ Designated as safety issue: No ]
• Suicidality [ Time Frame: Measured over 6 months ] [ Designated as safety issue: Yes ]

Bipolar illness, a brain disorder that causes dramatic changes in a person's mood and energy, affects about 2.6% of adults in the United States. Bipolar disorder is characterized by cyclical periods of extreme highs and lows, known as episodes of mania and depression. A person undergoing an episode of mania often experiences euphoric moods, increased energy, and aggressive behaviors, while a person in a depressed state often experiences low moods, lack of energy, and feelings of sadness. Lithium is a widely used mood stabilizing medication that has been shown to reduce the occurrence and intensity of manic episodes and may lessen depressive episodes as well. Including lithium as a part of a personalized medication treatment approach may be the most effective means of improving symptoms of bipolar disorder. This study will evaluate whether lithium included as part of optimized medication treatment improves overall level of illness, symptoms of mania and depression, and quality of life in people with bipolar disorder.

Participation in this study lasted for 6 months. All participants had an initial assessment that included an interview and questionnaires to confirm a diagnosis of bipolar disorder, vital sign measurements, a blood draw, and if female, pregnancy. Eligible participants were then assigned randomly to receive either optimized medication plus lithium or optimized medication without lithium. Participants in both groups received 6 months of monitored treatment with their medication regimens, as prescribed by their study doctor. Participants attended study visits every 2 weeks for the first 8 weeks and then once a month for 4 more months. These visits lasted between 45 and 60 minutes and included medication adjustments and questions about symptoms, side effects, and quality of life.

We would like to acknowledge that medication was kindly donated by Ortho-McNeil Janssen Scientific Affairs, LLC.

• Drug: Lithium Carbonate
  Lithium was started at 300 mg and then increased to 600 mg after 3 days. Lithium doses were maintained at 600 mg per day for 8 weeks, but may have been adjusted after that time as needed up to a serum level of 1.2 mEq/L.
  Other Name: Lithium
• Drug: Optimized Treatment (OPT)
  The foundation of OPT was to maintain treatment that will typically include at least one FDA-approved mood stabilizer other than lithium (e.g., divalproex, carbamazepine, risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone) and to follow the recommendations summarized in the evidence-based stages of the Texas Implementation of Medication Algorithm (TIMA) revised guidelines.

• Experimental: 1
  Participants received lithium plus optimized medication treatment, as needed.
  Interventions:

  • Drug: Lithium Carbonate
  • Drug: Optimized Treatment (OPT)
• Active Comparator: 2
  Participants only received optimized medication treatment, as needed; lithium was not be used.
  Intervention: Drug: Optimized Treatment (OPT)

• Ostacher MJ, Nierenberg AA, Rabideau D, Reilly-Harrington NA, Sylvia LG, Gold AK, Shesler LW, Ketter TA, Bowden CL, Calabrese JR, Friedman ES, Iosifescu DV, Thase ME, Leon AC, Trivedi MH. A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR). J Psychiatr Res. 2015 Dec;71:126-33. doi: 10.1016/j.jpsychires.2015.10.004. Epub 2015 Oct 9.
• Reilly-Harrington NA, Sylvia LG, Leon AC, Shesler LW, Ketter TA, Bowden CL, Calabrese JR, Friedman ES, Ostacher MJ, Iosifescu DV, Rabideau DJ, Thase ME, Nierenberg AA. The Medication Recommendation Tracking Form: a novel tool for tracking changes in prescribed medication, clinical decision making, and use in comparative effectiveness research. J Psychiatr Res. 2013 Nov;47(11):1686-93. doi: 10.1016/j.jpsychires.2013.07.009. Epub 2013 Jul 30.
• Beech RD, Leffert JJ, Lin A, Sylvia LG, Umlauf S, Mane S, Zhao H, Bowden C, Calabrese JR, Friedman ES, Ketter TA, Iosifescu DV, Reilly-Harrington NA, Ostacher M, Thase ME, Nierenberg A. Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS). Pharmacogenomics J. 2014 Apr;14(2):182-91. doi: 10.1038/tpj.2013.16. Epub 2013 May 14.
• Nierenberg AA, Friedman ES, Bowden CL, Sylvia LG, Thase ME, Ketter T, Ostacher MJ, Leon AC, Reilly-Harrington N, Iosifescu DV, Pencina M, Severe JB, Calabrese JR. Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium. Am J Psychiatry. 2013 Jan;170(1):102-10. doi: 10.1176/appi.ajp.2012.12060751.
• Sylvia LG, Reilly-Harrington NA, Leon AC, Kansky CI, Ketter TA, Calabrese JR, Thase ME, Bowden CL, Friedman ES, Ostacher MJ, Iosifescu DV, Severe J, Keyes M, Nierenberg AA. Methods to limit attrition in longitudinal comparative effectiveness trials: lessons from the Lithium Treatment - Moderate dose Use Study (LiTMUS) for bipolar disorder. Clin Trials. 2012 Feb;9(1):94-101. doi: 10.1177/1740774511427324. Epub 2011 Nov 10.

Inclusion Criteria:

• Meets DSM-IV Criteria for bipolar disorder (type I or II)
• Currently symptomatic, as defined as a Clinical Global Impressions Scale-Bipolar Version, Overall Severity Index (CGI-BP-S) of greater than or equal to 3
• If taking or has taken lithium, must be off lithium for at least 30 days before study entry
• If a woman of child bearing potential, agrees to inform their doctor at the earliest possible time of their plans to conceive, to use adequate contraception (e.g. oral contraceptives, intrauterine device, barrier methods, total abstinence from intercourse), and to acknowledge the risks of lithium to the fetus and infant (Depo Provera is acceptable if it is started 3 months before study entry)

Exclusion Criteria:

• Renal impairment (serum creatinine greater than 1.5 mg/dL)
• Thyroid stimulating hormone (TSH) over 20% above the upper normal limit (participants maintained on thyroid medication must be euthyroid for at least 3 months before Visit 1)
• History of lithium toxicity that was not caused by mismanagement or overdose
• Other contraindication to lithium (e.g., hypersensitivity to lithium or any component of the formulation, severe cardiovascular or renal disease, severe debilitation, dehydration, sodium depletion, pregnancy)
• Currently in crisis such that inpatient hospitalization or other crisis - Participated in a clinical trial of an investigational drug within the 1 months before study entry
• Pregnant or breastfeeding